tbuckley/cabot-search huggingface dataset:
NCOG-16. REAL-WORLD ANALYSIS OF OUTCOMES OF PATIENTS RECEIVING BEVACIZUMAB FOR RECURRENT GLIOBLASTOMA
Authors: Manik Chahal, Rebecca Harrison, Elaine Ni Mhurchu, Brian Thiessen
Journal: Neuro-Oncology (2022)

Abstract Bevacizumab has been publicly funded in British Columbia (BC) since 2011 for treatment of recurrent glioblastoma (rGBM). We performed a retrospective analysis of patients with rGBM treated with bevacizumab to evaluate treatment practices and outcomes. 245 patients with rGBM treated at BC Cancer centers with bevacizumab between January 2011 and December 2019 were reviewed. Patient demographics, tumor characteristics, treatment regimens, and dates and type of radiographic progression and death were collected. Kaplan-Meier method was used to assess overall survival from time of bevacizumab initiation (BevOS), and comparisons were made using the log-rank test. Median OS was 7 months (CI95 = 6.28-7.73) from bevacizumab initiation. 66% of patients on corticosteroids prior to bevacizumab reduced their dose, and performance status was the same or improved in 84% of patients shortly after initiation, suggesting improvement in quality of life. Patients started on bevacizumab &amp;lt; 6 months from chemoradiation (prior to completion of adjuvant temozolomide) had improved BevOS compared to those who started bevacizumab later (p = 0.019), but there was no association between extent of treatment prior to bevacizumab and outcomes (p = 0.417). Additionally, patients who had local progression prior to bevacizumab initiation had improved BevOS compared to those who had distant progression (p = 0.004), suggesting that pseudoprogression may have prompted the therapeutic switch. Furthermore, though there were no differences in baseline characteristics for patients treated at high volume centers vs. low volume centers, patients treated at high volume centers had improved BevOS (p = 0.004), potentially due to differences in expertise between centers or other social determinants of health not captured in baseline demographics. Together, these data highlight the need for optimization of patient selection and bevacizumab administration in high and low volume centers.
NCMP-19. VON HIPPEL-LINDAU DISEASE ASSOCIATED INTRACRANIAL HEMANGIOBLASTOMAS IN PREGNANCY: TREATMENT CHALLENGES AND OUTCOMES
Authors: Nanuli Gvazava
Journal: Neuro-Oncology (2022)

Abstract Von Hippel-Lindau disease is an autosomal dominant disorder characterized by development of variety of benign and malignant tumors and cysts including brain stem, cerebellum, spinal cord as well as pancreas, kidneys, and retina. The most common tumors associated with the disorder are hemangioblastomas. Symptomatic CNS hemangioblastomas maybe the first presentation of Von Hippel-Lindau disease. Initial presentation during pregnancy is uncommon and presents unique challenges with regard to early diagnosis and management. We report a case of a young woman with cerebellar hemangioblastoma, complicated by obstructive hydrocephalus, who first presented with signs and symptoms of increased intracranial pressure during pregnancy and was eventually diagnosed with Von Hippel-Lindau disease. We propose increase on size of Von Hippel-Lindau disease related hemangioblastomas during pregnancy and explore the pathophysiology of this disorder. Specific diagnostic challenges imposed by pregnancy and approach to management of these complex patients are also reviewed. Increase in tumor size as well as rare but life-threatening complications such as tumor hemorrhage are most likely to happen during the 3rd trimester of pregnancy. Unfortunately, non-specific symptoms like nausea and vomiting, which are common obstetric complaints, can be confounding and pose challenges to early diagnosis. Careful neurological examination is critical in pregnant patients with new onset neurological symptoms. When a hemangioblastoma is suspected, pregnant patients should be screened for Von Hippel-Lindau disease to identify other potentially life-threatening tumors, and when near term, elective delivery should be considered to avoid both maternal and fetal complications. In complicated cases such as obstructive hydrocephalus, CSF diversion may be indicated and will result in rapid symptom improvement and prevention of severe neurologic sequelae. Unlike sporadic hemangioblastomas, surveillance may be the preferred approach in Von Hippel-Lindau in the absence of symptoms, as these patients have multiple tumors and a high risk of recurrence, making repeat surgeries of unclear benefit.
NIMG-81. EFFECT OF RE-TREATMENT WITH TEMOZOLOMIDE IN GRADE 2/3 IDH MUTANT GLIOMAS AT FIRST PROGRESSION
Authors: Lalanthica Yogendran, Salma Abbas, Zachary Scharf, Sohil Patel, David Schiff
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Patients with WHO grade 2 and 3 IDHmt gliomas commonly receive temozolomide, with or without radiation therapy, as initial therapy. At progression, temozolomide is sometimes reinstated despite a paucity of data on effectiveness. METHODS We reviewed imaging outcomes of patients with grade 2/3 IDHmt gliomas re-treated with temozolomide at first progression between 2007 and 2019. RESULTS 15 subjects included six grade 2 and five grade 3 oligodendrogliomas, one grade 2 and three grade 3 astrocytomas. Median time between completion of first temozolomide course and initiation of re-treatment was 47 months (range, 8-126 months). Best treatment response after first progression by RANO criteria was stable disease in 10 and progressive disease in 5 patients. Median progression free survival with temozolomide re-treatment was 27.4 months (95% CI: [13.8, 41.2 months] and median overall survival 47.8 months (95% CI: [31.5, 125.6 months]). In 14 patients who had pre- and post- first tumor progression rate measurements, the mean rate of tumor growth by bidimensional product was 0.29 cm2/month (95% CI: [0.17, 0.42 cm2/month], p&amp;lt; 0.001) prior to first tumor progression versus 0.47 cm2/month (95 CI: [0.08, 0.85 cm2/month], p=0.021) during re-treatment with monotherapy temozolomide (prior vs after, p=0.371). The volumetric mean rate of tumor growth was 1.12 cc/month (95% CI: [0.31, 1.93 cc/month], p=0.010) prior to first tumor progression versus 1.29 cc/month (95% CI: [0.15, 2.43 cc/month], p=0.030) during temozolomide re-treatment (prior vs. after, p=0.802). CONCLUSION Among 15 patients with progressive IDHmt glioma re-treated with temozolomide, there was no radiographic response by RANO criteria nor a decrease in tumor growth rate during the re-treatment period compared to immediate pre-re-treatment period. These findings suggest previously treated, progressive IDHmt gliomas are generally resistant to temozolomide, underscoring the need for novel therapies.
CSIG-21. EXPLORING THE PHENOTYPIC EFFECTS OF TOLL SIGNALING PATHWAYS IN TUMOR PROGRESSION IN EGFR-DRIVEN GLIOBLASTOMA MODELS
Authors: Julia G Saborio, Riley Gulbronson, Elizabeth E Young, Irene Hsu, Renee D Read
Journal: Neuro-Oncology (2022)

Abstract The treatment options for Glioblastoma (GBM) are currently limited to resection and chemotherapy approaches, but resistance to chemotherapy is common in patients. There is an urgent need for further understanding of the underlying biology of tumorigenesis in order to develop new treatment options. Previous genomic work on GBMs has shown that the epidermal growth factor receptor (EGFR) is frequently amplified and constitutively active in GBM tumors. To discover new factors that contribute to progression of EGFR-driven GBMs, we used our Drosophila GBM model in which GBM-like glial neoplasia can be induced by glial-specific overexpression of constitutively active forms of EGFR and dp110, a subunit of Phosphoinositide 3-kinase (PI3K), using the UAS-GAL4 gene expression system. Using our Drosophila GBM model system, we performed a modifier screen in which we searched for genes and pathways that worsened or ‘enhanced’ glial neoplasia when specifically overexpressed or activated in neoplastic glia. From our screen, we identified the Toll pathway, which in Drosophila activates an NF-κB signaling pathway. Furthermore, the Toll pathway normally functions in innate immune and injury responses as well as in development and cell proliferation. Using our Drosophila GBM model, we are studying how the Toll signaling pathway and its effectors, including NF-κB, contribute to enhanced growth of neoplastic glial cells. Furthermore, using well-defined mouse genetic models and human patient-derived GBM models, we are examining whether Toll pathway regulatory and signaling mechanisms that we have uncovered in Drosophila function in EGFR-mutant GBM tumor stem cells to promote GBM progression and chemotherapy resistance.
BIOM-52. DIAGNOSTIC POTENTIAL OF EXTRACELLULAR VESICLES IN MENINGIOMA PATIENTS
Authors: Franz Ricklefs, Cecile Maire, Kathrin Wollmann, Lasse Dührsen, Krystian Fita, Felix Sahm, Christel Herold-Mende, Andreas von Deimling, Marceline Fuh, Hartmut Schlüter, Manfred Westphal, Katrin Lamszus
Journal: Neuro-Oncology (2022)

Abstract Standard monitoring after meningioma resection relies on serial MRI examinations, which are time-consuming, expensive and provide no information on molecular alterations that may indicate progression towards a more aggressive tumor. Extracellular vesicles (EVs) secreted by tumor cells play an important role in cell-cell communication, and tumor-derived EVs circulating in patient blood can serve as biomarkers. We investigated the potential role of plasma EVs in meningioma patients for tumor detection and determined whether EVs secreted by meningioma cells reflect epigenetic, genomic and proteomic alterations of original tumors. EV concentrations were quantified in patient plasma (n = 46). Short-term meningioma cultures were established (n = 26) and secreted EVs were isolated. Methylation and copy number profiling was performed using 850k arrays, and mutations were identified by targeted gene panel sequencing. Differential quantitative mass spectrometry was employed for proteomic analysis. We found that the levels of circulating EVs were significantly elevated in meningioma patients compared to healthy individuals, and that plasma EV concentrations correlated with malignancy grade and extent of peritumoral edema. Postoperatively, EV counts dropped to normal levels, and the magnitude of the postoperative decrease was associated with extent of tumor resection (Simpson grade). Methylation profiling of EV-DNA allowed correct tumor classification as meningioma in all investigated cases, and accurate methylation subclass assignment in nearly all cases. Copy number variations present in tumors, as well as tumor-specific mutations were faithfully reflected in meningioma EV-DNA. Proteomic EV profiling did not permit original tumor identification but revealed tumor-associated proteins such as desmoplakin that could potentially be utilized to enrich meningioma EVs from biofluids. In conclusion, elevated EV levels in meningioma patient plasma may aid in tumor diagnosis and assessment of treatment response. Meningioma EV-DNA mirrors genetic and epigenetic tumor alterations and facilitates molecular tumor classification.
CNSC-07. MECHANISMS OF GLIOBLASTOMA-INDUCED CORTICAL REMODELING IDENTIFY THERAPEUTIC VULNERABILITIES
Authors: Saritha Krishna, Abrar Choudhury, Michael Keough, Lijun Ni, Kyounghee Seo, Alexander Aabedi, Galina Popova, Sofia Kakaizada, Anne Findlay, Anthony Lee, Cesar Gonzales, Rasika Sudharshan, Caroline Cao, Humsa Venkatesh, Nyle Almeida, Srikantan Nagarajan, Mitchel S Berger, David Raleigh, David Brang, Michelle Monje, Shawn L Hervey-Jumper
Journal: Neuro-Oncology (2022)

Abstract Prior work demonstrated synaptic integration of malignant gliomas into neural circuits induces local hyperexcitability and tumor proliferation. However, prognostication and therapeutic vulnerabilities are lacking from preclinical models. Here, we integrate in vivo and in vitro neurophysiology spatially matched with gene expression programs and protein signaling mechanisms across 66 IDH WT glioblastoma patients to identify thrombospondin-1 (TSP-1) as a molecular driver of glioma-induced network remodeling. Bulk and single cell RNA-sequencing of 11 intratumoral regions maintaining functional connectivity (13,730 cells analyzed) revealed a distinct neurogenic signature enriched for the synaptogenic factor TSP-1. Mechanistic and functional studies validating therapeutic vulnerabilities to TSP-1 silencing by shRNA knockdown and FDA-approved inhibitors (Gabapentin and LSKL) of excitatory synapse formation through the gabapentin a2d-1 receptor was performed in vitro and in vivo. Glioma-neuron co-culture of TSP-1 overexpressing cells demonstrated increased Ki67 proliferation and tumor microtube (TMT) formation when cultured in the presence of neurons. Pharmacological inhibition of TSP-1 using gabapentin or TSP-1 shRNA inhibited the proliferation and TMT-mediated expansion. Hippocampal xenografted mice with TSP-1 over expressing primary patient cultures demonstrated shorter survival and gabapentin treatment of xenografted mice significantly reduced the proliferation of TSP-1 overexpressing cells in vivo. Electrophysiological properties of glioma-neuron co-cultures analyzed using multi-electrode array (MEA) demonstrated increased neuronal spiking activity and network burst synchrony in the presence of TSP-1 over expressing cells. Strikingly, these increases were eliminated in the presence of gabapentin. We modeled survival risk in patients incorporating the effects of glioma intrinsic neuronal activity, molecular, therapeutic, and clinical factors on overall survival by recursive partitioning. Three risk groups were identified based on tumor intrinsic neuronal activity, pre- and post-operative tumor volume with shortest overall survival in patients with glioma intrinsic neuronal activity. These data identify glioma-induced secretion of TSP-1 as a key contributor of tumor proliferation shedding light on new therapies.
INNV-25. ASSESSING SLEEP AND CIRCADIAN RHYTHMS IN PRIMARY BRAIN TUMORS PATIENTS: AN OBSERVATIONAL STUDY
Authors: Alex Wollet, Heather Leeper, Elizabeth Vera, Kelly Mentges, Amanda King, James Rogers, Dilorom (Delia) Sass, Alvina Acquaye, Kendra Adegbesan, Lisa Boris, Eric Burton, Orieta Celiku, Claudia Chambers, Anna Choi, Alexa Christ, Julianie Cruz De Le Minyety, Karen Evans, Ewa Grajkowska, Edina Komlodi-Pasztor, Jason Levine, Matthew Lindsley, Nicole Lollo, Tito Mendoza, Hope Miller, Marissa Panzer, Marta Penas-Prado, Valentina Pillai, Lily Polskin, Jennifer Reyes, Kayla Roche, Solmaz Sahebjam, Macy Stockdill, Brett Theeler, Kathleen Wall, Jing Wu, Mark Gilbert, Terri Armstrong, Dorela Shuboni-Mulligan
Journal: Neuro-Oncology (2022)

Abstract Sleep-wake disturbances are among the most common and severe symptoms in primary brain tumor (PBT) patients. Currently, no studies have quantified their physiological sleep measurements or compared these assessments to established patient reported outcome measures (PROs). Smart wearable devices, such as Fitbits, continuously monitor patient behaviors at home and provide detailed physiological measurements of sleep, activity, and heart rate. We hypothesized that smart wearable devices can accurately determine physiological sleep disturbances and circadian disruptions and will complement established PROs in a PBT patient population. This observational, cross-sectional trial monitors sleep and circadian rhythm variables using Fitbit smart wearable devices worn for 1 month. Additionally, participants will answer PROs questionnaires (PROMIS Sleep Disturbance and Sleep Related Impairment-Short Forms, Sleep Hygiene Index, Morningness-Eveningness questionnaire, and Consensus Sleep Diary) at study entry and during the last week on-study. The present study is a planned interim analysis of 54 patients to assess feasibility, including evaluation of enrollment, attrition, study parameter completion and data missingness. 73 PBT patients were screened and approached. Of these patients, 54 (74%) were enrolled on study and 19 (26%) declined participation (8 lacked interest, 3 discomfort wearing watches, 3 lacked smart phone, 2 unable to wear device at work, 2 unable to attend consent calls, 1 pregnancy and 1 cognitive complication). The accrued patients were 56% male, 56%³ 50 years of age, and 81% had a KPS³ 90. Patients represented different stages of treatment: 6% of patients were newly diagnosed, 24% on active treatment (11% 1st recurrence, 13% 2nd recurrence), and 70% were on imaging surveillance. Feasibility was confirmed as there were no deviations reported and 100% of PROs and study timepoints completed. Quantified Fitbit data including percent time worn and physiologic sleep parameters will be reported. Study enrollment for efficacy measures continues.
INNV-20. INCORPORATING EXPERT OPINIONS INTO THE DEVELOPMENT OF FEARLESS: A PSYCHOTHERAPEUTIC INTERVENTION TARGETING FEAR OF CANCER RECURRENCE IN THOSE WITH BRAIN TUMORS
Authors: Ashlee Loughan, Sarah Braun, Autumn Lanoye, Kelcie Willis
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION A brain tumor diagnosis brings about emotional distress, including significant fear of cancer recurrence (FCR). Three evidence-based interventions that target FCR exist, but all excluded patients with brain tumors (PwBT) from their efficacy trials. Preliminary evidence suggests that FCR may be categorically different in PwBT compared to other cancer populations, thereby necessitating tailored intervention development. For these reasons, we convened a neuro-oncology Expert Advisory Board (EAB) to assist in the creation of a psychotherapeutic intervention targeting FCR in PwBT. METHODS The EAB included neuro-oncology professionals, patients, and caregivers (N=7). To facilitate open dialogue, the patients and caregivers (n=3) met separately from the professionals (n=4). The EAB met virtually over five consecutive weeks to discuss three evidence-based FCR manuals, identify topic applicability, determine medical relevance, and discuss necessary adaptations to meet the specific needs of PwBT. Readings were provided in advance, two moderators (ARL &amp; SEB) led group discussions, and all sessions were recorded following consent. RESULTS The EAB determined the content contained in the three FCR intervention required tailoring to meet the distinct needs of PwBT. Hypervigilance patterns were determined to be unique for PwBT (e.g., headache, fatigue, word-finding, auras). Language surrounding uncertainty of progression and inclusion of healthcare providers in therapy were less relevant in PwBT. Strategies and skills to enhance acceptance of existential themes were spotlighted. Mindfulness practices were requested. Results called for a blend of three therapeutic orientations: cognitive behavioral therapy, existential therapy, and mindfulness-based therapy. Professionals promoted group intervention delivery, whereas patients and caregivers promoted individual or dyadic sessions. Caregiver participation was unanimously supported. CONCLUSION The development of a psychotherapeutic intervention targeting FCR in PwBT offers a distinct opportunity for interdisciplinary and community collaboration. Results from the EAB were overwhelmingly informative, and recommendations will be incorporated into the newly developed FCR intervention for PwBT: FearLess.
BIOM-66. MULTIPARAMETRIC QUALITIES OF PLASMA EXTRACELLULAR VESICLES AS NOVEL DIAGNOSTIC BIOMARKERS FOR GLIOBLASTOMA
Authors: Abudumijiti(Zack) Aibaidula, Cori Fain, Luz Cumba Garcia, Miyeon Jung, Aaron Johnson, Ian Parney
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Plasma extracellular vesicles (EVs) have been shown as a promising source for biomarker identification in glioblastoma (GBM) and could help differential diagnosis, treatment evaluation and tumor progression monitoring. These EVs are enriched in molecular signatures indicative of their cell origins, giving an indication of the key players in this pathology. In this project, we aimed to identify diagnostic biomarkers for GBM plasma EVs and their cells of origin. METHODS: Plasma EV samples were prepared following the MIFlowCyt-EV guideline of the International Society for Extracellular Vesicles, then stained for EV markers (CD9/CD63/CD81) and markers indicative of cell origins (CD31/CD45/CD41a/CD11b). Actin phalloidin was used as a negative marker. Stained plasma samples were analyzed using a Cytek Aurora flow cytometer. Percentages of different EV subpopulations were analyzed and compared between GBM and normal donor (ND) plasma EVs (reference group). Further clustering analysis was performed on EV events by t-distributed stochastic neighbor embedding (t-SNE) and self-organizing maps on flow cytometry data (FlowSOM) analysis. The predictive value of multiparametric qualities derived from the reference group was tested in blinded test group samples. RESULTS: Percentages of CD9, CD81, and CD11b positive EVs were higher in GBM patient plasma, while ND plasma had more CD41a positive EVs. GBM plasma EVs had unique multiparametric signatures compared to ND plasma EVs based on t-SNE and FlowSOM analysis. Our analysis also identified 15 distinct EV subpopulations which differed in size and various surface marker expression levels. Eight of these subpopulations were enriched for GBM EVs, while three were enriched for ND EVs. Our method of multiparametric analysis demonstrates high sensitivity and specificity in predicting disease status in human samples. CONCLUSIONS: GBM plasma EVs have a unique surface marker expression profile and distinct EV subpopulations compared to ND plasma EVs. Multiparametric signatures show promise as potential diagnostic markers of GBM.
SURG-40. SINGLE-STAGE RECONSTRUCTION FOLLOWING ONCOLOGIC RESECTION OF BRAIN TUMORS WITH SKULL INVASION
Authors: Netanel Ben-Shalom, Asemota Anthony, Belzberg Micah, Sagi Harnof, Judy Huang, Michael Lim, Henry Brem, Chad Gordon
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Craniectomies requiring skull reconstruction are indicated following oncological resection of masses involving the underlying brain and/or skull. Immediate cranioplasties have previously been performed using suboptimal hand-bending or molding techniques using ‘‘off – the – shelf’’ products. Today with computer – aided design, customized craniofacial implants have become widely available for personalized reconstruction of resected bone and soft tissue. We present the largest series to date of single stage reconstruction using alloplastic biomaterials in consecutive patient series with oversized customized implants.In total, 56 patients underwent resection of skull neoplasms and subsequent cranioplasty reconstruction using customized implants. The most common neoplasms were meningiomas (39%). The most common complications seen among patients were dehiscence – (7%), and extrusion of implant – (3.5%). There was no significant difference in the incidence of postoperative complications between patients who had postoperative chemotherapy/radiotherapy versus those that did not (22.2% versus 13.1%, P 0.39). One-year follow-up revealed acceptable cranial contour and symmetry in all 56 cases.